Multistage chemical carcinogenesis in mouse skin.
Skin tumors in mice can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct-acting carcinogen or a procarcinogen which has to be metabolized before being active; it is essentially an irreversible step which probably involves a somatic cell mutation as evidenced by a good correlation between the carcinogenicity of many chemical carcinogens and their mutagenic activities. There is a good correlation between the skin-tumor-initiating activities of several polycyclic aromatic hydrocarbons (PAH) and their ability to bind covalently to epidermal DNA. Results from our laboratory as well as others suggest that "bay region" diol-epoxides are the ultimate carcinogenic form of PAH carcinogens. Potent inhibitors and stimulators of PAH tumor initiation appear to affect the level of the PAH diol-epoxide reacting with specific DNA bases. REcent data suggest that the tumor-promotion stage involves at least 3 important steps: (1) the induction of embryonic-looking cells (dark cells) in adult epidermis; (2) an increased production of epidermal prostaglandins and polyamines; (3) sustained proliferation of dark cells. Retinoic acid specifically inhibits step 2, whereas the anti-inflammatory steroid fluocinolone acetonide is a potent inhibitor of steps 1 and 3. The mechanism and the importance of a specific sequence for each step in chemical carcinogenesis in mouse skin will be discussed in detail.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000037:antagonists & inhibitors; D000818:Animals; D001580:Benzopyrenes / Q000494:pharmacology; D003043:Cocarcinogenesis; D004247:DNA / Q000096:biosynthesis; D004224:Diterpenes; D004817:Epidermis / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D010703:Phorbol Esters / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011073:Polyamines / Q000096:biosynthesis; D012878:Skin Neoplasms / Q000139:chemically induced*; D013729:Terpenes
D001580:Benzopyrenes; D004224:Diterpenes; D010703:Phorbol Esters; D011073:Polyamines; D013729:Terpenes; C011309:mezerein; D015127:9,10-Dimethyl-1,2-benzanthracene; D004247:DNA